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Tepper, Sandra; Mortusewicz, Oliver; Czlonka, Ewelina; Bello, Amanda; Schmidt, Angelika; Jeschke, Julia; Fischbach, Arthur; Pfeil, Ines; Petersen-Mahrt, Svend K.; Mangerich, Aswin; Helleday, Thomas; Leonhardt, Heinrich; Jungnickel, Berit (2019): Restriction of AID activity and somatic hypermutation by PARP-1. In: Nucleic Acids Research, Vol. 47, No. 14: pp. 7418-7429
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Abstract

Affinity maturation of the humoral immune response depends on somatic hypermutation (SHM) of immunoglobulin (Ig) genes, which is initiated by targeted lesion introduction by activation-induced deaminase (AID), followed by error-prone DNA repair. Stringent regulation of this process is essential to prevent genetic instability, but no negative feedback control has been identified to date. Here we show that poly(ADP-ribose) polymerase-1 (PARP-1) is a key factor restricting AID activity during somatic hypermutation. Poly(ADP-ribose) (PAR) chains formed at DNA breaks trigger AID-PAR association, thus preventing excessive DNA damage induction at sites of AID action. Accordingly, AID activity and somatic hypermutation at the Ig variable region is decreased by PARP-1 activity. In addition, PARP-1 regulates DNA lesion processing by affecting strand biased A:T mutagenesis. Our study establishes a novel function of the ancestral genome maintenance factor PARP-1 as a critical local feedback regulator of both AID activity and DNA repair during Ig gene diversification.